Methods and devices for inducing collapse in lung regions fed by collateral pathways

ABSTRACT

Disclosed are methods and devices for treating a patient&#39;s lung region. A catheter is deployed into the lung. The catheter is used to apply heat to a targeted lung region wherein the heat affects fluid flow within the targeted lung region.

REFERENCE TO PRIORITY DOCUMENTS

This application is a continuation of co-pending U.S. patent applicationSer. No. 10/384,899 entitled “Methods and Devices for Inducing Collapsein Lung Regions Fed by Collateral Pathways”, filed Mar. 6, 2003, whichclaims priority of U.S. Provisional Patent Application Ser. No.60/363,328 entitled “Methods and Devices for Inducing Collapse in LungRegions Fed by Collateral Pathways”, filed Mar. 8, 2002. Priority of theaforementioned filing dates is hereby claimed, and the disclosures ofthe aforementioned patent application are hereby incorporated byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to methods and devices for use inperforming pulmonary procedures and, more particularly, to proceduresfor treating various diseases of the lung.

2. Description of the Related Art

Pulmonary diseases such as chronic obstructive pulmonary disease (COPD)reduce the ability of one or both lungs to fully expel air during theexhalation phase of the breathing cycle. The term “Chronic ObstructivePulmonary Disease” (COPD) refers to a group of diseases that share amajor symptom, dyspnea. Such diseases are accompanied by chronic orrecurrent obstruction to air flow within the lung. Because of theincrease in environmental pollutants, cigarette smoking, and othernoxious exposures, the incidence of COPD has increased dramatically inthe last few decades and now ranks as a major cause ofactivity-restricting or bed-confining disability in the United States.COPD can include such disorders as chronic bronchitis, bronchiectasis,asthma, and emphysema. While each has distinct anatomic and clinicalconsiderations, many patients may have overlapping characteristics ofdamage at both the acinar (as seen in emphysema) and the bronchial (asseen in bronchitis) levels, almost certainly because one pathogenicmechanism—cigarette smoking is common to both. (Robbins eds.,Pathological Basis of Disease, 5^(th) edition, pg 683)

Emphysema is a condition of the lung characterized by the abnormalpermanent enlargement of the airspaces distal to the terminalbronchiole, accompanied by the destruction of their walls, and withoutobvious fibrosis. It is known that emphysema and other pulmonarydiseases reduce the ability of one or both lungs to fully expel airduring the exhalation phase of the breathing cycle. One of the effectsof such diseases is that the diseased lung tissue is less elastic thanhealthy lung tissue, which is one factor that prevents full exhalationof air. During breathing, the diseased portion of the lung does notfully recoil due to the diseased (e.g., emphysematic) lung tissue beingless elastic than healthy tissue. Consequently, the diseased lung tissueexerts a relatively low driving force, which results in the diseasedlung expelling less air volume than a healthy lung. The reduced airvolume exerts less force on the airway, which allows the airway to closebefore all air has been expelled, another factor that prevents fullexhalation.

The problem is further compounded by the diseased, less elastic tissuethat surrounds the very narrow airways that lead to the alveoli (the airsacs where oxygen-carbon dioxide exchange occurs). This tissue has lesstone than healthy tissue and is typically unable to maintain the narrowairways open until the end of the exhalation cycle. This traps air inthe lungs and exacerbates the already-inefficient breathing cycle. Thetrapped air causes the tissue to become hyper-expanded and no longerable to effect efficient oxygen-carbon dioxide exchange. One way ofdeflating the diseased portion of the lung is to applying suction tothese narrow airways. However, such suction may undesirably collapse theairways, especially the more proximal airways, due to the surroundingdiseased tissue, thereby preventing successful fluid removal.

In addition, hyper-expanded lung tissue occupies more of the pleuralspace than healthy lung tissue. In most cases, a portion of the lung isdiseased while the remaining part is relatively healthy and thereforestill able to efficiently carry out oxygen exchange. By taking up moreof the pleural space, the hyper-expanded lung tissue reduces the amountof space available to accommodate the healthy, functioning lung tissue.As a result, the hyper-expanded lung tissue causes inefficient breathingdue to its own reduced functionality and because it adversely affectsthe functionality of adjacent, healthier tissue.

Lung volume reduction surgery is a conventional method of treating lungdiseases such as emphysema. According to the lung reduction procedure, adiseased portion of the lung is surgically removed, which makes more ofthe pleural space available to accommodate the functioning, healthierportions of the lung. The lung is typically accessed through a mediansternotomy or lateral thoracotomy. A portion of the lung, typically theupper lobe of each lung, is freed from the chest wall and then resected,e.g., by a stapler lined with bovine pericardium to reinforce the lungtissue adjacent the cut line and also to prevent air or blood leakage.The chest is then closed and tubes are inserted to remove fluid from thepleural cavity. The conventional surgical approach is relativelytraumatic and invasive, and, like most surgical procedures, is not aviable option for all patients.

Some recently proposed treatments include the use of devices thatisolate a diseased region of the lung in order to reduce the volume ofthe diseased region, such as by collapsing the diseased lung region.According to such treatments, isolation devices are implanted in airwaysfeeding the targeted region of the lung to isolate the region of thelung targeted for volume reduction or collapse. These implantedisolation devices can be, for example, one-way valves that allow flow inthe exhalation direction only, occluders or plugs that prevent flow ineither direction, or two-way valves that control flow in bothdirections. However, even with the implanted isolation devices properlydeployed, air can flow into the isolated lung region via a collateralpathway. This can result in the diseased region of the lung stillreceiving air even though the isolation devices were implanted into thedirect pathways to the lung. Collateral flow can be, for example, airflow that flows between segments of a lung, or it can be, for example,air flow that flows between lobes of a lung, as described in more detailbelow.

Collateral flow into an isolated lung region can make it difficult toachieve a desired flow dynamic for the lung region. Moreover, it hasbeen shown that as the disease progresses, the collateral flowthroughout the lung can increase, which makes it even more difficult toproperly isolate a diseased lung region by simply implanting flowcontrol valves in the bronchial passageways that directly feed air tothe diseased lung region.

In view of the foregoing, there is a need for a method and device forregulating fluid flow to and from a region of a lung that is suppliedair through a collateral pathway, such as to achieve a desired flowdynamic or to induce collapse in the lung region.

SUMMARY

Disclosed are methods and devices for regulating fluid flow to and froma lung region that is supplied air through one or more collateralpathways, such as to induce collapse in the lung region or to achieve adesired flow dynamic. In accordance with one aspect of the invention,there is disclosed a method of regulating fluid flow for a targeted lungregion, comprising identifying at least one collateral pathway thatprovides collateral fluid flow into the targeted lung region andperforming an intervention within the lung to reduce the amount ofcollateral fluid flow provided to the targeted lung region through thecollateral pathway. The method can also include identifying at least onedirect pathway that provides direct fluid flow into the targeted lungregion and deploying a bronchial isolation device in the direct pathwayto regulate fluid flow to the targeted lung region through the directpathway.

Also disclosed is a method of regulating fluid flow for a targeted lungregion, comprising reducing direct fluid flow in a direct pathway thatprovides direct fluid flow to the targeted lung region; and reducingcollateral fluid flow that flows through a collateral pathway to thetargeted lung region.

Also disclosed is a method of treating a patient's lung region,comprising deploying a catheter into a lung; and using the catheter toapply heat to a targeted lung region wherein the heat affects fluid flowwithin the targeted lung region.

Other features and advantages of the present invention should beapparent from the following description of various embodiments, whichillustrate, by way of example, the principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an anterior view of a pair of human lungs and abronchial tree.

FIG. 2 illustrates a lateral view of the right lung.

FIG. 3 illustrates a lateral view of the left lung.

FIG. 4 illustrates an anterior view of the trachea and a portion of thebronchial tree.

FIG. 5 illustrates an anterior view of a lung having a lung lobe that isreceiving collateral air flow through a collateral pathway comprised ofan incomplete interlobar fissure.

FIG. 6 illustrates an anterior view of a lung having a lung segment thatis receiving collateral air flow.

FIG. 7 illustrates the delivery of a flowable therapeutic agent to atargeted lung region using a balloon-tipped delivery catheter.

FIG. 8 illustrates the delivery of a flowable therapeutic agent to atargeted lung region using a delivery catheter.

FIG. 9 illustrates the percutaneous injection of a flowable therapeuticagent to a targeted lung region.

FIG. 10 illustrates the injection of a flowable therapeutic agent into atargeted lung region through a catheter that has a sharpened tip.

FIG. 11 illustrates the deployment of a delivery catheter in a patientusing a bronchoscope.

FIG. 12 illustrates a lateral view of the right lung, showing a targetedlung region and an adjacent healthy lung region.

FIG. 13 illustrates the injection of a therapeutic agent into a targetedlung region, controlled by applied pressure in an adjacent lung region.

FIG. 14 illustrates the treatment of collateral flow paths using abeta-emitting radiation source.

FIG. 15 illustrates the treatment of collateral flow paths usingflow-limiting isolation devices.

FIG. 16 illustrates the percutaneous suction of a targeted lung regionusing a suction catheter.

FIG. 17 illustrates the sealing of collateral flow paths between theright upper lobe and the right middle lobe through the use of a two-partadhesive.

FIG. 18 illustrates the use of shunt tubes that are mounted in bronchialpassageway to provide free air pathways to a targeted lung region.

FIG. 19 is a cross-sectional view of a flow control element that allowsfluid flow in a first direction but blocks fluid flow in a seconddirection.

FIG. 20 shows a perspective view of another embodiment of a flow controlelement.

FIG. 21 shows a cross-sectional, perspective view of the flow controlelement of FIG. 21.

FIG. 22 shows a valve element.

FIG. 23 shows a side view of the valve element of FIG. 22.

FIG. 24 shows a cross-sectional view of the valve element of FIG. 22along the line 24-24 of FIG. 23.

FIG. 25 shows an enlarged, sectional view of the portion of the flowcontrol element contained within line 25 of FIG. 22.

DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the invention(s) belong.

Disclosed are methods and devices for regulating fluid flow to and froma region of a patient's lung, such as to achieve a desired fluid flowdynamic to a lung region during respiration and/or to induce collapse inone or more lung regions that are supplied air through one or morecollateral pathways. An identified region of the lung (referred toherein as the “targeted lung region”) is targeted for flow regulation,such as to achieve volume reduction or collapse. The targeted lungregion is then bronchially isolated to regulate fluid flow to thetargeted lung region through bronchial pathways that directly feed fluidto the targeted lung region. If a desired flow characteristic to thetargeted region is not achieved, or if the targeted lung region does notcollapse after bronchially isolating the targeted lung region, then itis possible that a collateral pathway is feeding air to the targetedlung region. The collateral flow can prevent the targeted lung regionfrom collapsing. In such a case, the collateral pathway is identifiedand an intervention is performed within the lung to modify or inhibitfluid flow into the targeted lung region via the collateral pathway,such as according to the methods described herein. While the inventioncan involve such treatment of collateral flow pathways in combinationwith bronchial isolation, it should be understood that the invention mayalso be practiced without bronchial isolation in some circumstances.Further, the invention also encompasses temporary bronchial isolationwhile treating lung regions fed by collateral pathways.

Exemplary Lung Regions

Throughout this disclosure, reference is made to the term “lung region”.As used herein, the term “lung region” refers to a defined division orportion of a lung. For purposes of example, lung regions are describedherein with reference to human lungs, wherein some exemplary lungregions include lung lobes and lung segments. Thus, the term “lungregion” as used herein can refer, for example, to a lung lobe or a lungsegment. Such nomenclature conform to nomenclature for portions of thelungs that are known to those skilled in the art. However, it should beappreciated that the term lung region does not necessarily refer to alung lobe or a lung segment, but can refer to some other defineddivision or portion of a human or non-human lung.

FIG. 1 shows an anterior view of a pair of human lungs 110, 115 and abronchial tree 120 that provides a fluid pathway into and out of thelungs 110, 115 from a trachea 125, as will be known to those skilled inthe art. As used herein, the term “fluid” can refer to a gas, a liquid,or a combination of gas(es) and liquid(s). For clarity of illustration,FIG. 1 shows only a portion of the bronchial tree 120, which isdescribed in more detail below with reference to FIG. 4.

Throughout this description, certain terms are used that refer torelative directions or locations along a path defined from an entrywayinto the patient's body (e.g., the mouth or nose) to the patient'slungs. The path of airflow into the lungs generally begins at thepatient's mouth or nose, travels through the trachea into one or morebronchial passageways, and terminates at some point in the patient'slungs. For example, FIG. 1 shows a path 102 that travels through thetrachea 125 and through a bronchial passageway into a location in theright lung 110. The term “proximal direction” refers to the directionalong such a path 102 that points toward the patient's mouth or nose andaway from the patient's lungs. In other words, the proximal direction isgenerally the same as the expiration direction when the patientbreathes. The arrow 104 in FIG. 1 points in the proximal or expiratorydirection. The term “distal direction” refers to the direction alongsuch a path 102 that points toward the patient's lung and away from themouth or nose. The distal direction is generally the same as theinhalation or inspiratory direction when the patient breathes. The arrow106 in FIG. 1 points in the distal or inhalation direction.

The lungs include a right lung 110 and a left lung 115. The right lung110 includes lung regions comprised of three lobes, including a rightupper lobe 130, a right middle lobe 135, and a right lower lobe 140. Thelobes 130, 135,140 are separated by two interlobar fissures, including aright oblique fissure 126 and a right transverse fissure 128. The rightoblique fissure 126 separates the right lower lobe 140 from the rightupper lobe 130 and from the right middle lobe 135. The right transversefissure 128 separates the right upper lobe 130 from the right middlelobe 135.

As shown in FIG. 1, the left lung 115 includes lung regions comprised oftwo lobes, including the left upper lobe 150 and the left lower lobe155. An interlobar fissure comprised of a left oblique fissure 145 ofthe left lung 115 separates the left upper lobe 150 from the left lowerlobe 155. The lobes 130, 135, 140, 150, 155 are directly supplied airvia respective lobar bronchi, as described in detail below.

FIG. 2 is a lateral view of the right lung 110. The right lung 110 issubdivided into lung regions comprised of a plurality ofbronchopulmonary segments. Each bronchopulmonary segment is directlysupplied air by a corresponding segmental tertiary bronchus, asdescribed below. The bronchopulmonary segments of the right lung 110include a right apical segment 210, a right posterior segment 220, and aright anterior segment 230, all of which are disposed in the right upperlobe 130. The right lung bronchopulmonary segments further include aright lateral segment 240 and a right medial segment 250, which aredisposed in the right middle lobe 135. The right lower lobe 140 includesbronchopulmonary segments comprised of a right superior segment 260, aright medial basal segment (which cannot be seen from the lateral viewand is not shown in FIG. 2), a right anterior basal segment 280, a rightlateral basal segment 290, and a right posterior basal segment 295.

FIG. 3 shows a lateral view of the left lung 115, which is subdividedinto lung regions comprised of a plurality of bronchopulmonary segments.The bronchopulmonary segments include a left apical segment 310, a leftposterior segment 320, a left anterior segment 330, a left superiorsegment 340, and a left inferior segment 350, which are disposed in theleft lung upper lobe 150. The lower lobe 155 of the left lung 115includes bronchopulmonary segments comprised of a left superior segment360, a left medial basal segment (which cannot be seen from the lateralview and is not shown in FIG. 3), a left anterior basal segment 380, aleft lateral basal segment 390, and a left posterior basal segment 395.

FIG. 4 shows an anterior view of the trachea 125 and a portion of thebronchial tree 120, which includes a network of bronchial passageways,as described below. In the context of describing the lung, the terms“pathway” and “lumen” are used interchangeably herein. The trachea 125divides at a lower end into two bronchial passageways comprised ofprimary bronchi, including a right primary bronchus 410 that providesdirect air flow to the right lung 110, and a left primary bronchus 415that provides direct air flow to the left lung 115. Each primarybronchus 410, 415 divides into a next generation of bronchialpassageways comprised of a plurality of lobar bronchi. The right primarybronchus 410 divides into a right upper lobar bronchus 417, a rightmiddle lobar bronchus 420, and a right lower lobar bronchus 422. Theleft primary bronchus 415 divides into a left upper lobar bronchus 425and a left lower lobar bronchus 430. Each lobar bronchus, 417, 420, 422,425, 430 directly feeds fluid to a respective lung lobe, as indicated bythe respective names of the lobar bronchi. The lobar bronchi each divideinto yet another generation of bronchial passageways comprised ofsegmental bronchi, which provide air flow to the bronchopulmonarysegments discussed above.

As is known to those skilled in the art, a bronchial passageway definesan internal lumen through which fluid can flow to and from a lung. Thediameter of the internal lumen for a specific bronchial passageway canvary based on the bronchial passageway's location in the bronchial tree(such as whether the bronchial passageway is a lobar bronchus or asegmental bronchus) and can also vary from patient to patient. However,the internal diameter of a bronchial passageway is generally in therange of 3 millimeters (mm) to 10 mm, although the internal diameter ofa bronchial passageway can be outside of this range. For example, abronchial passageway can have an internal diameter of well below 1 mm atlocations deep within the lung.

Direct and Collateral Flow

Throughout this disclosure, reference is made to a “direct pathway” to atargeted lung region and to a “collateral pathway” to a targeted lungregion. The term “direct pathway” refers to a bronchial passageway thatbranches directly or indirectly from the trachea and either (1)terminates in the targeted lung region to thereby directly provide airto the targeted lung region; or (2) branches into at least one otherbronchial passageway that terminates in the targeted lung region tothereby directly provide air to the targeted lung region. The term“collateral pathway” refers to any pathway that provides air to thetargeted lung region and that is not a direct pathway. The term “direct”is used to refer to air flow that flows into or out of a targeted lungregion via a direct pathway. Likewise, the term “collateral” is used torefer to fluid flow (such as air flow) that flows into or out of atargeted lung region via a collateral pathway. Thus, for example,“direct” flow is fluid flow (such as air flow) that enters or exits thetargeted lung region via a direct pathway, and “collateral” flow isfluid flow (such as air flow) that enters or exits the targeted lungregion via a collateral pathway.

A collateral flow can be, for example, air flow that flows betweensegments of a lung, which is referred to as intralobar flow, or it canbe, for example, air flow that flows between lobes of a lung, which isreferred to as interlobar flow. One exemplary process of identifying acollateral pathway that provides collateral air flow into a targetedlung region is described below.

In accordance with one aspect of the disclosed methods, a targetedregion of the lung is identified, wherein the targeted lung region cancomprise, for example, a single one of the lung regions described abovewith reference to FIGS. 1-3, or the targeted lung region can comprise acollection of the regions described above. Alternately, the targetedlung region can be some other portion of the lung. The targeted lungregion can be, for example, a diseased lung region for which it isdesired to bronchially isolate the region for the purposes of inhibitingfluid flow into the region. As used herein, to “bronchially isolate” alung region means to modify the flow to the targeted lung region, suchas to regulate, prevent, or inhibit direct air flow to the lung region.In one embodiment, after the targeted lung region is identified, anattempt is made to bronchially isolate the targeted lung region, such asby occluding the bronchial pathway(s) that directly feed air to thetargeted lung region. This may be accomplished, for example, byadvancing and implanting a bronchial isolation device into the one ormore bronchial pathways that directly feed air to the targeted lungregion to thereby regulate direct flow into the lung region.

The bronchial isolation device can be, for example, a device thatregulates the flow of air into a lung region through a bronchialpassageway. Some exemplary bronchial isolation devices comprised of flowcontrol elements are described in detail below with reference to FIG.19-25. In addition, the following references describe exemplary flowcontrol elements: U.S. Pat. No. 5,594,766 entitled “Body Fluid FlowControl Device; U.S. patent application Ser. No. 09/797,910, entitled“Methods and Devices for Use in Performing Pulmonary Procedures”; andU.S. patent application Ser. No. 10/270,792, entitled “Bronchial FlowControl Devices and Methods of Use”. The foregoing references are allincorporated herein by reference in their entirety and are all assignedto Emphasys Medical, Inc., the assignee of the instant application.

If the targeted lung region does not collapse, then it can be assumedthat the targeted lung region is not collapsing because of collateralair flow into the lung. In such a case, it is desirable to modifycollateral flow into the targeted lung region in order to encouragecollapse or to achieve a desired flow dynamic for the lung region. Forexample, the collateral flow into the targeted lung region can becompletely prevented so that there is no collateral flow into thetargeted lung region. Alternately, the collateral flow into the targetedlung region can simply be reduced, such as to minimize the effect of thecollateral flow on the targeted lung region.

Use of Flowable Therapeutic Agents to Reduce or Prevent Collateral Flow

One way of impeding collateral fluid flow into the targeted lung regionis by injecting one or more flowable therapeutic agents into thetargeted lung region in order to partially or completely seal thecollateral pathway(s) that are providing collateral flow into thetargeted lung region. The agent is “flowable” in that the agent is atleast initially in a fluid state, which can be, for example, a liquid,gas, aerosol, etc. The agent is “therapeutic” in that, when the agentcontacts lung tissue, the agent generates a reaction in the tissue ofthe targeted lung region that serves to reduce, inhibit, or preventcollateral fluid flow into the targeted lung region. The reaction canresult in, for example (1) gluing or sealing portions of the targetedlung region together to thereby seal collateral pathways; (2) sclerosingor scarring target lung tissue to thereby occlude the collateralpathway(s) and seal off collateral flow into the targeted lung region;(3) promoting fibrosis in or around the targeted lung region to therebyseal off collateral flow into the region; (4) creating of aninflammatory response that would seal or fuse collateral pathway(s) thatlead into the targeted lung region; (5) or creation of a bulking agentthat fills space (such as space within the targeted lung region and/orthe collateral pathway) and thereby partially or entirely seal offcollateral flow into the targeted lung region.

A variety of flowable therapeutic agents have been identified thatachieve one or more of the above reactions in lung tissue. The agentsinclude, for example, the following:

(1) a foam created from either synthetic materials or natural biologicalmaterials that has one or more of the following-described properties.According to one property, the foam expands in volume from an initialinjected volume to an expanded volume by a predetermined volume amount.For example, the foam may double in volume from an injected volume toexpanded volume. Such volume expansion would cause the foam to fill-upand seal the volume of the targeted lung region or the volume of acollateral pathway. According to another property, the foam can beresorbable or degradable in the tissue of a patient's body, such that,when the foam is injected into the targeted lung region, the targetedlung region would absorb the foam and shrink in volume. For example, thefoam could comprise a biodegradable polymer, such as polyethylene glycol(PEG) or polyglycolic acid (PGA). In another example, the foam could bea biodegradable polymer that is foamed with hydrogen or some other gasand that is permeable through the cellular structure of the foam.

When a foam as described above is injected into the targeted lungregion, gas would begin to diffuse out of the foam matrix, which wouldcause cells within the foam to collapse. As the foam collapses, theadjacent tissue will be drawn to a smaller volume simultaneously due toadhesion between the foam and the surrounding tissue. In one embodiment,the foam has balanced properties of flow and viscosity in order toincrease the likelihood that the foam will adequately fill the targetedlung region. Such balanced properties would also reduce the likelihoodof the foam running or leaking into regions of the lung adjacent to thetargeted lung region through the collateral pathway(s). The foam canretain a foamy consistency until it is absorbed into the lung tissue, orit can cure and harden and then dissolve over time.

(2) A sealant or glue, such as, for example, fibrin, fibrinogen andthrombin epoxy, various cyanoacrylate adhesives and sealants, such asn-butyl-2-cyanoacrylate, synthetic biocompatible sealants made frompolyethylene polymers, etc.

(3) Sclerosing agents such as, for example, doxycycline, minocycline,tetracycline, bleomycin, cisplatin, doxorubicin, fluorouracil,interferon-beta, mitomycin-c, Corynebacterium parvum,methylprednisolone, and talc.

(4) Antibiotics such as, for example, doxycycline, minocycline orbleomycin, tetracycline, etc.

(5) Bulking agents such as, for example, collagen, gelatin, Gelfoam, orSurgicel solutions, polyvinyl acetate (PVA), ethylene vinyl alcoholcopolymer (EVAL) or ethylene vinyl alcohol copolymer solutions.

One example of an appropriate bulking material is the Onyx LiquidEmbolic System manufactured by Micro Therapeutics, Irvine, Calif. Thismaterial is ethylene vinyl alcohol copolymer combined with micronizedtantalum powder for fluoroscopy contrast dissolved in dimethl sulfoxide(DMSO) solvent. It solidifies through precipitation upon contact with anaqueous solution, such as saline, and forms a spongy mass.

(6) Agents for inducing a localized infection and scar such as, forexample, a weak strain of Pneumococcus.

(7) Other agents such as mucolytics (to reduce or eliminate mucus),steroids, factor XIIIa transglutaminase.

(8) Fibrosis promoting agents such as a polypeptide growth factor(fibroblast growth factor (FGF), basic fibroblast growth factor (bFGF),transforming growth factor-beta (TGF-β))

(9) Pro-apoptopic agents such as sphingomyelin, Bax, Bid, Bik, Bad,caspase-3, caspase-8, caspase-9, or annexin V.

(10) Components of the extracellular matrix (ECM) such as hyaluronicacid (HA), chondroitin sulfate (CS), fibronectin (Fn), or ECM-likesubstances such as poly-L-lysine or peptides consisting of praline andhydroxyproline.

Any well-known radiopaque contrast agent could be added to thetherapeutic agent in order to facilitate viewing of the agent as it isdispersed in the targeted lung region. A sufficient quantity of agent isdispersed to seal collateral pathways, but not so much that adjacenttissue is affected. The flowable therapeutic agents that can be used tolimit collateral flow into a targeted lung region are not limited tothose described above.

Identification of Regions for Treatment

As discussed above, the targeted lung region can be an entire lobe ofone of the lungs 110, 115, or the targeted lung region can be one ormore lung segments, such as, for example, the lung segments describedabove with reference to FIGS. 2 and 3. In the case of the targeted lungregion being a lung lobe, an attempt is made to bronchially isolate thetarget lobe by sealing the direct pathways(s) into the target lobe, suchas by implanting a bronchial isolation device into the lobar bronchusthat supplies air to the targeted lobe. If the targeted lobe still doesnot collapse, then it can be assumed that a collateral pathway issupplying air to the targeted lobe, wherein the collateral pathway isthrough an incomplete interlobar fissure. The outer surface of the lungis covered with a serous membrane called the visceral pleura. When thefissure between lobes is complete, the two adjacent lobes are separatedand are completely covered with visceral pleura of all surfaces, andthere is no collateral air flow possible between lobes. When the fissureis incomplete, the adjacent lobes are not completely separated, thevisceral pleura does not completely surround the lobes, and parenchymafrom the adjacent lobes in the incomplete portion of the fissure touchand are not separated. This incomplete formation of the fissure occursnaturally in about 50% of fissures in human lungs, and collateral airflow can occur between the lobes through these regions. See, Raasch B N,et al. Radiographic Anatomy of the Interlobar Fissure: A Study of 100Specimens. AJR 1982;138:1043-1049. When there is collateral airflowthrough an incomplete interlobar fissure thereby preventing collapse ofthe treated lobe, the lung can be treated to cause the fissure to seal(either partially or entirely) and thereby reduce or prevent collateralflow into the targeted lung lobe via the interlobar fissure.

FIG. 5 shows an example of a lung lobe that has been bronchiallyisolated using a bronchial isolation device comprised of a flow controlelement, which regulates fluid flow through a bronchial passageway thatsupplies fluid to the lobe. The lobe receives collateral air flowthrough a collateral pathway comprised of an incomplete interlobarfissure. As shown in FIG. 5, a bronchial isolation device 510, such aflow control element, is implanted in the right middle lobar bronchus420 in order to prevent direct flow into the targeted lung regioncomprised of the right middle lobe 135. However, the right middle lobe135 is still receiving collateral flow (as exhibited by a series ofarrows 512 in FIG. 5) through a collateral pathway comprised of anincomplete right transverse fissure 128. The collateral flow comes fromthe right upper lobar bronchus 417 and passes into the right middle lobe135 through the incomplete right transverse fissure 128. Thus, the rightupper lobar bronchus 417 can also be considered to be a portion of thecollateral pathway into the right middle lobe 135. The collateral flowinto the right middle lobe 135 could be prevented or reduced by sealingthe air pathways through the incomplete right transverse fissure 128where the middle lobe 135 contacts the inferior surface of the rightupper lobe 130.

In another exemplary scenario, the targeted lung region can be aspecific lung segment or some other portion of the lung that is within alobe. In this case, an attempt is made to bronchially isolate thetargeted lung segment (or other portion of the lung), such as byinserting a flow control element into the direct pathway(s) to thetargeted lung segment. If the targeted lung segment still does notcollapse, it can be assumed that the flow is originating from other lungsegments or other regions within the same lobe as the targeted segment,or from an incomplete interlobar fissure that is adjacent to thetargeted lung segment. FIG. 6 shows an example of this scenario. Asshown in FIG. 6, a targeted lung segment 610 is located within the rightupper lobe 130. The targeted lung segment 610 can receive direct flowvia segmental bronchus 615. The targeted lung segment 610 also receivescollateral flow from an adjacent segment 620 that is also located withinthe right upper lobe 130.

In another example with reference to FIG. 6, a targeted lung segment 630is located in the right upper lobe 130 adjacent to the right transversefissure 128. The targeted lung segment 630 can receive collateral flowfrom an adjacent lung segment in the right upper lobe 130. The targetedlung segment 130 can also receive collateral flow from the right middlelobe 135 via an incomplete right transverse fissure 128, in which case abronchial passageway of the right middle lobe 135 is the source of thecollateral flow.

If collateral flow to a targeted lung segment is originating from othersegments or regions within the same lobe as the targeted lung region, oris originating from a separate, adjacent lobe via an incomplete fissure,it might be necessary to determine the bronchial passageway that issupplying collateral flow to the targeted lung region. One method ofdetermining the magnitude of collateral flow, using selective bronchialballoon catheterization combined with ventilation on a helium-basedmarker gas and a helium detector, is disclosed in the literature. See,Morrell N W, et al. Collateral Ventilation and Gas Exchange inEmphysema, Am J Respir Crit Care Med 1994;150:635-41.

One technique of identifying the bronchial passageway(s) that feed theparenchyma that communicates through the incomplete interlobar fissurewith the targeted lung portion is now described. According to thistechnique, the bronchial sub-branches, such as segmental bronchi,feeding parenchyma adjacent to the interlobar fissure of an isolatedlobe are determined fluoroscopically utilizing a standard guide wire.The following example illustrates the technique as applied in the rightupper lobe, although the same principles could be used in any of thehuman lung's five lobes or any segments within those lobes. Although thelung is 3-dimensional and the airways are not sequentially related tolinear lung regions (e.g., the most inferior segmental bronchus maypartially feed the mid-section of a lung lobe or may preferentially feedthe anterior or posterior aspect of that lobe), the goal is to determinethe lowest (most inferior) sub-branch of the target upper lobe, as thissub-branch provides airflow to the lung parenchyma that borders thefissure between the upper lobe and the middle and lower lobes.

In a first step of the technique, a bronchoscope is passed through themost inferior bronchus as seen from a bronchoscopic perspective. This isperformed according to well-known methods using a standard bronchoscope.A guidewire is then passed through the working channel of thebronchoscope and visually fed into the subsequent, most inferiorsub-branches to the visual limits of the bronchoscope. The guidewire isthen advanced further with the aid of fluoroscopic visualization. Forinferior/superior determination, the fluoroscope will generally be in ananterior-posterior orientation (90 degrees to the patient's chest). Theposition of the guidewire relative to fluoroscopic landmarks (e.g.:relative to a rib or to the diaphragm) is then noted. The aforementionedsteps are repeated in multiple sub-branches until it can be determinedwhich bronchial sub-branch feeds the most inferior lung tissue (and thusadjacent to the interlobar fissure), and this sub-branch is selected fortreatment.

Utilizing a fully articulating C-arm (fluoroscope), these steps can berepeated in other views (e.g. the camera in a 90 degree lateral view foranterior/posterior position) to map the sub-branches in 3-dimensions. Inthis way, a physician can determine which bronchial sub-branch orbranches feed the most inferior lung tissue, tissue that borders theright middle and right lower lobes. This technique could be applied toany lobe in the lung, and to either the inferior or superior surfaces.

Delivery of Flowable Therapeutic Agent to Targeted Lung Region

The flowable therapeutic agent can be delivered to the targeted lungregion according to a variety of methods. Some exemplary methods ofdelivering a flowable therapeutic agent to the targeted lung region aredescribed below. Regardless of the method used, the therapeutic agentcan be delivered to the targeted lung region either before or after anattempt is made to bronchially isolate the targeted lung region using abronchial isolation device, or without bronchial isolation.

FIG. 7 illustrates an example of a method wherein a flowable therapeuticagent 705 is delivered to a targeted lung region using a deliverycatheter 710. The targeted lung region is located in the right middlelobe 135 of the right lung 110. The delivery catheter 710 can be aconventional delivery catheter of the type known to those of skill inthe art. The delivery catheter 710 is deployed in a bronchialpassageway, such as in the segmental bronchi 715, that leads to thetargeted lung region. The delivery catheter 710 is deployed such that adistal end of the catheter 710 is positioned distal of a bronchialisolation device 510 that has also been deployed in the bronchialpassageway 710. As mentioned, the bronchial isolation device 510 can bedeployed either before or after deployment of the delivery catheter 710.

Once the delivery catheter 710 is deployed in the targeted lung region,the flowable therapeutic agent 705 can be delivered into the targetedlung region using the delivery catheter 710. This can be accomplished bypassing the flowable therapeutic agent through an internal lumen in thedelivery catheter so that the agent exits a hole in the distal end ofthe delivery catheter 710 into the targeted lung region. As shown inFIG. 7, the distal end of the delivery catheter 710 can be sealed withinthe targeted lung region by inflating a balloon 720 that is disposednear the distal end of the catheter according to well-known methods. Inanother embodiment, shown in FIG. 8, the bronchial isolation device 510provides the sealing so that a balloon is not needed when delivering theflowable therapeutic agent 705 using the delivery catheter 710.

FIG. 9 illustrates another method of delivering the flowable therapeuticagent to the targeted lung region. According to the method shown in FIG.9, a delivery device, such as a delivery catheter or a hypodermic needle910, is used to percutaneously inject the flowable therapeutic agent 705directly into the lung tissue of the targeted lung region. Thehypodermic needle 910 is used to puncture the chest wall according towell-known methods so that a sharpened delivery tip 915 of the needle910 locates within the targeted lung region. For example, the targetedlung region could comprise a portion of the right middle lobe 135located near the fissure 128, as shown in FIG. 9. The hypodermic needle910 is then used to puncture the chest wall and the needle 910 ispositioned so that the delivery tip 915 locates within the right middlelobe 135. The flowable therapeutic agent 705 is then injected directlyinto the targeted lung region via the hypodermic needle 910 according towell-known methods.

FIG. 10 shows yet another method of delivering the flowable therapeuticagent to the targeted lung region. According to this method, a deliverycatheter 710 has a distal tip 1005 that can be used to puncture the wallof a bronchial passageway 1010 at a location that is at or near thetargeted lung region. The distal tip 1005 is configured to facilitatepuncturing of the bronchial wall, as described more fully below. Oncethe distal tip 1005 has been used to puncture the bronchial wall, thedistal tip of the delivery catheter 710 is passed through the bronchialwall and the flowable therapeutic agent can be injected into thetargeted lung region through the delivery catheter 710. The method shownin FIG. 10 differs from the method described above with reference toFIGS. 7 and 8 in that the method shown in FIG. 10 actually punctures thebronchial wall so that the flowable therapeutic agent can be injecteddirectly into the lung tissue. The method shown in FIGS. 7 and 8 doesnot include puncturing of the bronchial wall, and the flowabletherapeutic agent is injected into the bronchial lumen leading to thetargeted lung region rather than directly into the lung tissue.

The puncturing of the bronchial wall can be accomplished using any of avariety of methods and devices. According to one embodiment, the distaltip 1010 of the delivery catheter is configured to facilitate puncturingof the bronchial wall. For example, the distal tip 1005 can be sharpenedto an appropriate sharpness that will facilitate puncturing of abronchial wall. It has been determined that a delivery catheter with adiameter of up to 3 millimeters (mm) will be sufficient. Alternately, ahypodermic needle can be mounted on the distal tip 1005 to facilitatepuncturing of the bronchial wall. In another configuration, a stiffguidewire is delivered to the targeted lung region via the inner lumenof a flexible bronchoscope. The guidewire is then used to puncture thebronchial wall. After puncturing, a delivery catheter is delivered overthe stiff guidewire to the targeted lung region. In anotherconfiguration radio frequency (RF) energy is applied to a catheter thatcomprises an RF cutting tip, and the cutting tip is applied to thebronchial wall at a location at or near the targeted lung region,thereby causing the bronchial wall to puncture. A device approved forthis purpose is the Exhale RF Probe, Broncus Technologies, Inc. MountainView, Calif., FDA 510(k) #K011267. In yet another configuration, aflexible biopsy forceps is delivered through a working channel of thebronchoscope and used to cut a hole through the bronchial wall in awell-known manner.

The delivery catheter 710 can be deployed at the targeted lung regionaccording to a variety of methods. For example, with reference to FIG.11, the delivery catheter 710 can be deployed using a bronchoscope 1111,which in an exemplary embodiment has a steering mechanism 1115, adelivery shaft 1120, a working channel entry port 1125, and avisualization eyepiece 1130. The bronchoscope 1111 has been passed intoa patient's trachea 125 and guided into the right primary bronchus 410according to well-known methods. The delivery catheter 710 is thendeployed into the working channel entry port 1125 and down a workingchannel (not shown) of the bronchoscope shaft 1120, and the distal end1135 of the catheter 710 is guided to a desired location within thebronchial tree, such as to a lobar bronchi 417 located within the upperlobe 130 of the right lung 110. The steering mechanism 11 15 can be usedto deliver the shaft 1120 to a desired location.

Alternately, the delivery catheter 710 can have a central guidewirelumen and can be deployed using a guide wire that guides the catheter tothe delivery site. The delivery catheter 710 could have a well-knownsteering function, which would allow the catheter 710 to be deliveredwith or without use of a guidewire.

In yet another method of delivering the flowable therapeutic agent, oneor more nasal cannulae are deployed through a patient's nasal cavity,through the trachea, and to a desired location in the bronchial tree 120at the targeted lung region. One or more bronchial isolation devices,such as a flow control element, can also be deployed to bronchiallyisolate the targeted lung region, with a distal end(s) of the cannula(e)being passed through the bronchial isolation device(s). Alternately, acatheter with multiple divided lumens or cannulae could be deployed. Thecannula can be left in place for a desired amount of time and aninfusion of one or more flowable therapeutic agents is deployed to thetargeted lung region via the cannula. The flowable therapeutic agentscould be continuously or intermittently administered at a desired flowrate until the desired level of therapeutic effect has been obtained. Inanother embodiment, the delivery catheter 710 can be used to bronchiallyisolate the targeted lung region without the use of, or in combinationwith the use of, a flow control element. In such a case, the distal endof the delivery catheter 710 is equipped with a balloon (such as theballoon 720 shown in FIG. 7), which is inflated to occlude or partiallyocclude the bronchial passageway that provides fluid flow to thetargeted lung region. In this manner, fluid flow through the bronchialpassageway can be reduced or eliminated.

Controlling Dispersion of the Therapeutic Agent in the Lung

In the course of delivering the therapeutic agent to the targeted lungregion, it can be desirable to control the dispersion of the therapeuticagent in the lung so that the agent does not flow through any collateralpathways into areas of healthy lung tissue. It can also be desirable tomove the therapeutic agent preferentially toward the collateralpathway(s) (rather than toward some other area of the lung) in order toincrease the likelihood that sealing of collateral pathway(s) issuccessful.

One way of controlling the movement of the therapeutic agent within thelung is to provide pressure differentials in different regions of thelung, wherein the pressure differentials encourage the therapeutic agentto flow in a desired manner. For example, as shown in FIG. 12, atargeted lung region 1210 is located in the right lower lobe 140 of theright lung 110. A healthy lung region 1220 is located adjacent to thetargeted lung region 1210. The pressure within the targeted lung regionis P1 and the pressure within the adjacent lung region 1220 is P2. If P1is greater than P2, then a therapeutic agent located in the targetedlung region 1210 will be inclined to flow toward the adjacent lungregion 1220 due to the pressure differential. Likewise, if P2 is greaterP1, then a therapeutic agent located in the targeted lung region 1210will be inclined to flow away from the adjacent lung region 1220.

One way to accomplish such a pressure differential is to control theinjection pressure that is used to inject the therapeutic agent into thetargeted lung region, and to also control a back pressure in an adjacentlung region where collateral pathways to the targeted lung regionoriginate. If the therapeutic agent is radiopaque, a physician can viewthe extent of the therapeutic agent dispersion while also varying theinjection pressure and the back pressure to control the dispersion.

This is described in more detail with reference to FIG. 13, which showsa cross-sectional view of the right lung 110, wherein the targeted lungregion comprises the right middle lobe 135, which is adjacent to ahealthier lung region comprised of the right upper lobe 130. Theincomplete right transverse fissure 128 provides a collateral pathwaythrough which collateral flow originating in the right upper lobe 130passes into the right middle lobe 135. A first delivery catheter 710,which can have a balloon 720, is passed through a bronchial isolationdevice 510 so that the distal end of the catheter 710 is disposed in thetargeted lung region. A second catheter 1305 is deployed in a bronchialpassageway that provides flow to a lung region adjacent to the targetregion, wherein some collateral flow originates at the adjacent lungregion. For example, FIG. 13 shows the second catheter 1305 deployedthrough the right lobar bronchus 417, which provides flow to the rightupper lobe 130 where the collateral flow into the right middle lobeoriginates. The second catheter can have a balloon 1310 that isinflated.

The delivery catheter 710 is then used to inject the flowabletherapeutic agent 705 into the targeted lung region at a desiredinjection pressure. This will cause the targeted lung region to achievea pressure P1. While the therapeutic agent is being injected, a suctioncan be applied to the distal end of the second catheter 1305 to therebyachieve a pressure P2 in the adjacent lung region comprised of the rightupper lobe 130. By controlling the injection pressure and suction, adesired pressure differential between P1 and P2 can be achieved tothereby control the dispersion of the therapeutic agent. The pressuredifferential can be manipulated to encourage the therapeutic agent toflow toward the collateral pathway and even enter the collateralpathway. As discussed, the dispersion can be visually monitored if thetherapeutic agent includes a radiopaque.

When the desired dispersion level has been achieved, such as when thetherapeutic agent has filled the targeted lung region or has filled thecollateral pathways, it might then be desirable to further control thedispersion to reduce the likelihood that the therapeutic agent will flowinto the healthy lung region. This can be accomplished by again varyingthe pressure differential so that the therapeutic agent no longer flowstowards the healthy lung region. For example, the injection pressure canbe reduced or eliminated, while also changing the suction pressure atthe second catheter 1305. Suction can then be applied to the deliverycatheter 710 to remove any excess therapeutic agent from the targetedlung region. The catheters 710,1305 are then removed. In this manner,the therapeutic agent is preferentially moved toward the collateralpathway(s).

The aforementioned technique for sealing the collateral flow pathwaycould also be performed prior to the implantation of the bronchialisolation device(s) 510.

Follow-On Therapy After Treatment with Flowable Therapeutic Agent

After the infusion of the flowable therapeutic agents into the targetedlung region, a follow-on therapy procedure can be followed. According toone procedure, the treated portion of the lung (the portion of the lungto which the therapeutic agent was applied) is left alone, with thetherapeutic agent in place. The treated lung portion is allowed tocollapse by either absorption of the therapeutic agent by the body,absorption of the trapped gas in the isolated lung region, exhalation oftrapped gas out through a flow control device (such as an implantedone-way or two-way valve device) or any combination of these events.

According to another follow-on therapy procedure, the therapeutic agentis removed from the lung following the passage of a predeterminedtreatment period. The therapeutic agent could be removed after a shortperiod of time such as one or two minutes, or a longer period of 30 or60 minutes. Alternatively, if required, the therapeutic agent could beremoved in a separate procedure hours or days later. The necessary timeperiod would depend on the particular therapeutic agent used. This couldbe done with the implanted bronchial isolation devices in place, orcould be done before implantation of the bronchial isolation devices ifthe therapeutic agent was deployed prior to implantation of thebronchial isolation devices. The therapeutic agent can be removed fromthe lung in any number of ways, which include the following:

-   -   (a) Inflating a balloon catheter in the bronchial passageway        leading to the targeted lung region and aspirating through the        catheter central lumen. If bronchial isolation devices had been        implanted already, the suction in the catheter would pull the        excess therapeutic agent through the one-way or two-way valves        of the isolation devices. This method is likely not used where        the implanted devices are plugs or occluders.    -   (b) Crossing the implanted one-way or two-way valves with a        catheter and applying suction through the central lumen of the        catheter. The catheter could either be sealed by the valve in        the implanted device, or it could be a balloon catheter where        the balloon is inflated in the bronchial passageway distal to        the implanted device.    -   (c) Percutaneously suctioning the therapeutic agent directly out        of the lung tissue, such as by using a hypodermic needle.    -   (d) Suctioning the therapeutic agent out of the targeted lung        region through the a hole created in the bronchial wall. This        can be done using a new catheter or using the same catheter as        was used to inject the agent.

Thus, there have been disclosed several basic approaches to injecting aflowable therapeutic agent for preventing or reducing collateral flowinto a targeted lung region. Some examples of the basic approaches aresummarized as follows:

-   -   (a) Implant one or more bronchial isolation devices to isolate        targeted lung region; inject a flowable therapeutic agent into        the targeted lung region distal to the bronchial isolation        devices; allow the lung region to collapse, such as, for        example, by absorption of the therapeutic agent by the body,        absorption of the trapped gas in the isolated lung portion,        exhalation of trapped gas out through the implanted one-way or        two-way valve devices, or any combination of these events.    -   (b) Implant one or more bronchial isolation devices; inject a        flowable therapeutic agent into the targeted lung region distal        to devices;

wait a pre-determined treatment time period; remove the therapeuticagent, such as, for example, by using suction, needle aspiration, etc.;and

allow the lung region to collapse, such as, for example, by absorptionof the trapped gas in the isolated lung portion, exhalation of trappedgas out through the implanted one-way or two-way valve devices, or both.

-   -   (c) Inject a flowable therapeutic agent into the targeted lung        region;

implant bronchial isolation devices; allow the targeted lung region tocollapse, such as, for example, by absorption of the therapeutic agentby the body, absorption of the trapped gas in the isolated lung portion,exhalation of trapped gas out through the implanted one-way or two-wayvalve devices, or any combination of these events.

-   -   (d) Inject a flowable a therapeutic agent into parenchyma of the        targeted lung region; implant one or more bronchial isolation        devices; wait a pre-determined treatment time period; remove the        therapeutic agent, such as, for example, using suction, needle        aspiration, etc.; and allow lung region to collapse, such as,        for example, by absorption of the trapped gas in the isolated        lung portion, exhalation of trapped gas out through the        implanted one-way or two-way valve devices, or both.    -   (e) Inject a flowable therapeutic agent into the targeted lung        region; wait a pre-determined treatment time period; remove        therapeutic agent; implant bronchial isolation devices; and        allow the lung region to collapse.    -   (f) Temporarily isolate the targeted lung region; inject a        flowable therapeutic agent into the targeted lung region; wait a        pre-determined treatment time period; and remove therapeutic        agent.    -   (g) Temporarily isolate the targeted lung region; and inject a        flowable therapeutic agent into the targeted lung region.        Application of Energy to Reduce or Prevent Collateral Flow

An alternate way of reducing or preventing collateral fluid flow intothe targeted lung region is to apply energy to the targeted lung region,wherein the application of energy generates a reaction in the tissue ofthe targeted lung region that serves to reduce or prevent collateralfluid flow into the targeted lung region. The reaction can result in,for example: (1) gluing or sealing portions of the lung together tothereby partially or entirely seal collateral pathways; (2) sclerosingor scarring target lung tissue to thereby partially or entirely occludethe collateral pathway(s) and partially or entirely seal off collateralflow into the targeted lung region; (3) promoting fibrosis in or aroundthe targeted lung region to thereby partially or entirely seal offcollateral flow into the region; (4) creating of an inflammatoryresponse that would partially or entirely seal or fuse collateralpathway(s) that lead into the targeted lung region. A variety of energysources have been identified that can be used to apply energy to lungtissue to achieve any of the aforementioned reactions. The types ofenergy include Beta-emitting radiation, radio frequency energy, heat,ultrasound, cryo-ablation, laser energy, and electrical energy. Theprocess of identifying the lung region for treatment can be the same asthat described above with reference to the use of the flowabletherapeutic agent.

A variety of different methods can be used to deliver energy to adesired location in the targeted lung region. Regardless of the methodused, the therapeutic agent can be delivered to the targeted lung regioneither without bronchial isolation, or before or after an attempt ismade to bronchially isolate the targeted lung region using a bronchialisolation device.

FIG. 14 illustrates a method wherein an energy source is delivered to atargeted lung region using a delivery catheter 710. The targeted lungregion is located in the right middle lobe 135 of the right lung 110.The delivery catheter 710 can be a conventional delivery catheter of thetype known to those of skill in the art. The delivery catheter 710 isdeployed in a bronchial passageway, such as in the sub-segmental bronchi715, that leads to the targeted lung region. A distal end of thecatheter 710 is inserted into the bronchial passageway and is positioneddistal of a bronchial isolation device 510 that has been deployed in abronchial passageway that provides direct flow to the targeted lungregion. As discussed above, the bronchial isolation device 510 can bedeployed either before or after deployment of the delivery catheter 710.

Once the delivery catheter 710 is deployed in the targeted lung region,an energy source 1410 can be delivered into the targeted lung regionusing the delivery catheter 710. This can be accomplished, for example,by passing a push wire 1415 having a distally-mounted energy source 1410through an internal lumen in the delivery catheter 710 so that theenergy source 1410 exits a hole in the distal end of the deliverycatheter 710 into the targeted lung region. Alternately, the energysource 1410 can be mounted on the distal end of the delivery catheter710. The distal end of the delivery catheter 710 can be sealed withinthe targeted lung region by inflating a balloon that is disposed nearthe distal end of the catheter according to well-known methods.Alternately, the bronchial isolation device 510 can provide the sealingso that a balloon is not needed.

According to another method of delivering the energy, a delivery device,such as delivery catheter or a hypodermic needle, is used topercutaneously reach the targeted lung region by puncturing the chestwall and outer surface of the lung. The energy source is then advanceddirectly into the lung tissue. This would be similar to the method shownin FIG. 9, although an energy source would be used in place of theflowable therapeutic agent.

In yet another method of delivering the energy to the targeted lungregion, a delivery catheter has a distal tip that can be used topuncture the wall of a bronchial passageway that is located at or nearthe targeted lung region. The distal tip is configured to facilitatepuncturing of the bronchial wall. Once the distal tip's-has been used topuncture the bronchial wall, the energy source is advanced into thetargeted lung region through the delivery catheter. This would besimilar to the process shown in FIG. 10. The puncturing of the bronchialwall can be accomplished using any of a variety of methods and devices,such as was described above with reference to FIG. 10.

The delivery catheter for delivering the energy source to the targetedlung region could be deployed in the same manner described above withreference to the flowable therapeutic agents, such as by using abronchoscope.

Exemplary Method for Applying Energy to Targeted Lung Region

The delivery of beta-emitting radiation could be accomplished with abrachytherapy delivery system that includes a beta-emitting radiationsource mounted to the end of a delivery catheter, such as was describedabove. As mentioned previously, this could be done either before orafter the implantation of bronchial isolation devices.

According to one method of applying the energy, a betaradiation-emitting source is passed through one or more target bronchialpassageways, either sequentially or concurrently, that lead to thetargeted lung region. The source can also be passed through one or moreof the bronchial isolation devices that were previously implanted. Theradiation source is left in place for a period of time so as to elicit ascarring/healing response in the treated lung tissue. For example, itmay be discovered through animal and/or human clinical trials that anexposure time period of 30 minutes to one hour will achieve satisfactoryresults. A maximum time may be identified wherein the risk of radiationto the surrounding tissue is greater than the benefits of scarring thetarget tissue. For example, it may be discovered that the radiationsource can remain in up to an hour, but that exposure for greater than90 minutes increases risk to the patient.

In another application method, the application procedure is performedover a predetermined time period and/or over bronchial sub-branches. Forexample, a patient can first be admitted for a procedure to deploybronchial isolation devices, such as flow limiting valves, and thendischarged with periodic reassessment of anatomical or clinical results.The physician and patient could decide when the next step oftransvalvular brachytherapy should take place (e.g.: 15-30 days afterthe primary procedure). Brachytherapy could also be staged over time insuch a way as to minimize risk while continually assessing benefit(e.g.: valves placed day one, first brachytherapy procedure of 30minutes exposure day 30, second brachytherapy procedure of 30 minutes atday 60, etc.). The first brachytherapy session could be targeted at theRUL, inferior sub-segment of the anterior, segmental bronchus; thesecond session would target the RUL superior sub-segment of theanterior, segmental bronchus; etc.

The same procedures described above for beta-emitting radiation could befollowed for other radiation sources such as RF energy, heat,ultrasound, or cryo-ablation. These energy sources might requiredifferent treatment times, a different number of treatment sites, etc.,but the general application method would be the same.

Use of Flow-Limiting Isolation Devices to Limit Collateral Flow

Another way of impeding collateral fluid flow into the targeted lungregion is now described, wherein flow-limiting devices are implanted inthe bronchial passageway leading to lung regions adjacent to the targetregion, wherein the adjacent lung region that is not targeted forcollapse.

As with the previously described methods, the lung region targeted forisolation and collapse is identified, and bronchial isolation devicesare implanted in all airways that provide direct flow to the targetedlung region. The implanted isolation devices can be, for example,one-way valves that allow flow in the exhalation direction only, one-wayvalves that allow flow in the inhalation direction only, occluders orplugs that prevent flow in either direction, or two-way valves thatcontrol flow in both directions according to well-known methods. If thelung region does not collapse, such as due to either absorptionatelectasis, or through exhalation of trapped gas through the implanteddevices, then the lung region is likely being kept inflated throughcollateral in-flow through collateral pathways from adjacent lungregions. If the collateral flow from-the adjacent lung regions could bereduced substantially or eliminated, the targeted lung region willlikely collapse.

One way to reduce or substantially eliminate the collateral flow fromadjacent lung regions is to implant inhalation flow limiting two-wayvalve devices in the bronchial passageways leading to adjacent lungregions not targeted for collapse, wherein the adjacent lung regions actas a source for collateral flow into the targeted lung region. Suchdevices would allow free fluid flow in the exhalation direction for theadjacent lung regions, but would limit the flow to a predetermined levelin the inhalation direction. As a result, flow into the adjacent lungregion would be limited, thereby limiting the flow of gas into thetargeted lung region through the collateral pathways from the adjacentlung regions. The flow limitation is desirably sufficient to allow theisolated lung region to collapse, but would not collapse the adjacentlung regions. Once sufficient time had passed to allow the targeted lungregion to become chronically atelectatic, the flow limiting two-wayvalve devices could be removed from the adjacent lung regions in orderto restore normal ventilation to the lung portion not targeted forcollapse.

An example of this method is shown in FIG. 15, which shows a targetedlung region comprised of the right upper lobe 130 that is isolated byone-way bronchial isolation devices 510 that are implanted in allbronchial passageways leading to the lobe 130. The devices 510 areone-way valve devices that stop all flow in the inhalation direction tothereby prevent direct flow into the lobe 130. A flow limiting two-wayvalve bronchial isolation device 1510 is implanted in the bronchialpassageway in the right middle lobe 135 in the segment that lies justbelow the interlobar fissure 128 adjacent to the lobe 130. The device1510 allows free flow in the exhalation direction and a limited flow inthe inhalation direction. This limits the flow into the middle lobe 135,in a manner determined by the back flow restriction of the two-wayvalve. By limiting the flow into the middle lobe 135, the collateralflow into the targeted upper lobe 130 that originates in the middle lobe130 is also limited. The flow limitation into the middle lobe 135 issufficient to allow the right upper lobe 130 to collapse, as thecollateral flow into the upper lobe 135 via the fissure 128 isinsufficient to inflate the upper lobe 130.

One exemplary embodiment of a flow limiting two-way valve 2500 is shownin FIGS. 22-25. In this embodiment, the valve would behave as a one-wayvalve in the forward or exhalation direction in that it would allow freeflow of fluid through the valve. However, the valve would also allow acontrolled rate of flow in the reverse or inhalation direction. Thiscould be achieved in a duckbill style valve by adding a small flowchannel 2510 through the lips 2512 of the valve, as shown in FIG. 25.The reverse flow channel shown would allow fluid to flow in theinhalation direction, and the rate of flow would be controlled bydiameter and length of the flow channel.

Use of Percutaneous Suction to Limit Collateral Flow

Another method for limiting collateral flow into a targeted lung regionis through the use of percutaneous suction. As discussed, bronchialisolation devices may be implanted in any bronchial passageways thatprovide direct flow to the targeted lung region. Percutaneous suction isthen applied to the targeted lung region for a time period sufficient toadhere or fuse the lung tissue in the targeted lung region in acollapsed state such that the targeted lung region will not re-inflatethrough collateral pathways after the suction is stopped.

The percutaneous suction method is described in more detail withreference to FIG. 16, which shows the targeted lung region being locatedin the right upper lobe 130. An attempt is made to bronchially isolatethe targeted lung region by implanting one or more bronchial isolationdevices 705 in bronchial passageway that provide direct flow into thetargeted lung region. A suction catheter 1610 is percutaneously insertedinto the targeted lung region, such as by inserting the catheter 705through the rib space in a well-known manner. The suction catheter 1610includes an internal lumen and has a distal end 1615 on which arelocated one or more suction holes 1620 that communicate with theinternal lumen. A suction force can be applied to a proximal end 1625 ofthe catheter 1610 to suck fluid into the internal lumen through thesuction holes 1620 on the distal end 1615 of the catheter 1610. Afixation balloon 1630 is mounted on the catheter 1610 a short distancefrom the distal end 1615 of the catheter 1610. In one embodiment, thefixation balloon 1630 is mounted approximately 2 centimeters from thedistal end 1615. An exemplary suction catheter that can be used is the8-French Venography Catheter, manufactured by The Cook Group, Inc.,Bloomington, Ind.

As shown in FIG. 16, the suction catheter 1610 is percutaneouslyinserted into the targeted lung region so that the suction holes 1620 inthe distal end 1615 are positioned within the targeted lung region. Thefixation balloon 1630 is positioned in the pleural space of the lung andis then inflated to thereby fix the suction catheter 1610 in a fixedposition and to also seal the incision that was used to percutaneouslyinsert the catheter 1610. The suction catheter 1610 can be maneuveredinto the correct location using guidance assistance, such as computertomography (CT) or fluoroscopic guidance.

After the suction catheter 1610 has been properly positioned, a suctionforce can be applied to the internal lumen of the catheter to therebycause a sucking force that draws fluid into the internal lumen throughthe suction holes 1620. The suction force will draw air or other fluidin the targeted lung region into the internal lumen through the suctionholes 1620, which will aspirate the targeted lung region into acollapsed state. It has been determined that a suction force ofapproximately 100-160 mmHg is sufficient to aspirate the targeted lungregion into a collapsed state. The suction force can be continuouslymaintained for a time period sufficient to permanently collapse the lungand reduce the likelihood of inflation through collateral pathways. Inone embodiment, the suction is continuously maintained for a minimumtime period of eight hours. In another embodiment, the suction ismaintained for a time period of one to eight days. The suction can beperformed while the patient is on bed rest, using a stationary vacuumsource, or it could be performed using a portable vacuum source in orderto permit the patient to ambulate.

After the suction time period has elapsed, a flowable therapeutic agent(such as any of the agents described above) can optionally be infusedinto the targeted lung region. This could be performed using the suctioncatheter 1610, such as by infusing the agent through a separate internallumen located in the catheter 1610 or through the same lumen that wasused for suction. The therapeutic agent could be used to increase thelikelihood that the targeted lung region is properly sealed. Thefixation balloon 1630 is then deflated and the suction catheter 1610 isremoved.

Use of Two-Part Adhesive to Limit Collateral Flow

According to another method of inhibiting collateral flow into atargeted lung region, a two-part adhesive or glue is used to occlude acollateral pathway to the targeted lung region. The adhesive cancomprise a two-part mixture that includes a first part and a secondpart, wherein the first part and the second part collectively solidifywhen brought into contact with each other. The two parts do notnecessarily require complete mixing in order for the solidification tooccur. The solidification can be triggered, for example, by a catalyticreaction that occurs when the two parts contact one another. In oneembodiment, the two-part glue is a fibrin glue and the two parts of theglue are thrombin and fibrinogen.

A method for deploying a two-part adhesive in order to seal a collateralpathway is now described. The collateral pathway is located in a lungregion between two or more bronchial passageway, such as a firstbronchial passageway and a second bronchial passageway. For example, asshown in FIG. 17, the collateral pathway can be an incomplete interlobar128 fissure that is located between a first bronchial passageway 1710and a second bronchial passageway 1715. The bronchial passageway are notnecessarily in the same lobe. For example, in FIG. 17 the bronchialpassageway 1710 is in the right upper lobe 130 and the bronchialpassageway 1715 is in the right middle lobe 135, where the targeted lungregion is also located.

According to the method, the first part of the two-part adhesive isinjected into the first bronchial passageway and the second part of thetwo-part adhesive is injected into the second bronchial passageway. Theinjection pressure and flow rates of the first and second parts can becontrolled to encourage the first and second parts to flow to a commonlocation, wherein the common location coincides with the location of thecollateral flow path. That is, the first and second parts will contactone another within the collateral flow path. As mentioned, the first andsecond parts solidify when they contact one another. In this manner, thefirst and second parts solidify within the collateral flow path andthereby partially or entirely seal the collateral flow path.

An example of this is shown in FIG. 17, which shows a balloon-tippedcatheter 1712 that has been deployed in the second bronchial passageway1715, which supplies direct flow to the targeted lung region. Abronchial isolation device 510 is deployed in a segmental bronchus 1735that is proximal to the second bronchial passageway 1715 in order tobronchially isolate the targeted lung region. The catheter 1712 issealed within the bronchial passageway 1715 by inflating a balloon 1720mounted on the catheter 1712. A second balloon-tipped catheter 1725 isdeployed in the first bronchial passageway 1710 and sealed by inflatinga balloon 1730. The first part 1728 of the two-part adhesive is theninjected into the bronchial passageway 1715 via the catheter 1712 andthe second part 1732 of the two-part adhesive is injected into thebronchial passageway 1710 via the catheter 1725. The first and secondparts are injected in such a manner that they flow into the lung andmeet at the collateral pathway comprised of the incomplete interlobarfissure 128. As a result of the contact between the first and secondparts, they solidify within the interlobar fissure and thereby partiallyor entirely seal the interlobar fissure.

Once the adhesive has solidified, any remaining quantity of the firstand second parts can be suctioned out of the lung. Alternately, thefirst and second parts could be absorbable by the body so that excessmaterial need not be removed. The aforementioned technique for sealingthe collateral flow pathway could also be performed prior to theimplantation of the bronchial isolation device(s) 510.

Implanted Shunt Tubes

One of the major challenges with emphysematic patients is that certainbronchial passageways collapse during exhalation, thus leading toreduced flow through these lumens. This often results in trapped gas incertain regions of the lung that exhale air through the collapsed lumen.This in turn can lead to hyperinflation of the lung region, as well ascompression of the healthy lung tissue that is adjacent to the lungregion. One way of treating the hyperinflated lung region is to implantbronchial isolation devices, such as one-way or two-way valves, in thebronchial passageway that lead to the lung region in order to promotelung region collapse. However, the effectiveness of the bronchialisolation devices can be limited due to the reduced air flow duringexhalation through the native bronchial passageways, especially ifcollateral flow is present.

One method of counteracting this effect is to implant one or more shunttubes that are inserted through the bronchial passageways and into thetargeted lung region comprised of a damaged lung region. The shunt tubesprovide a clear flow path for exhaled air that is not be occluded by thecollapsed bronchial passageway. In order to collapse the targeted lungregion, one-way valves may be either mounted to a proximal end of theshunt tubes, or implanted in the bronchial passageways at some distanceproximal to the proximal end of the tubes. These valves allow exhaledair to escape in the exhalation direction through the valve or valves,but do not allow inhaled air to return to the isolated targeted lungregion. In this way, the targeted lung region eventually collapses aftersufficient air had been exhaled. Alternatively, a self expanding braidedtube can be used to prop the collapsed airway open. This allows sidebranches to continue to exhale air into the braided tube while keepingthe bronchi open.

FIG. 18 shows an example of how shunt tubes can be utilized. A bronchialisolation device 510 is implanted in a bronchial passageway of the rightupper lobe 130. Two implanted shunt tubes 1810 and 1820 are showndeployed in two lumens. The shunt tubes 1810, 1820 are located distal tothe implanted isolation device 510. The shunt tubes 1810, 1820 keep theairways open and provide a flow path through which exhaled air can pass.The implanted shunt tubes 1810 and 1820 are shown in FIG. 18 as beingimplanted just distally to the implanted bronchial isolation device 510.Alternatively, the shunt tubes may be implanted more distally, and agreater quantity may be implanted. The shunt tubes may be anchored inthe bronchial lumen in a number of ways. In a first embodiment, theshunt tube have spring resilience and expand when released from asmaller constrained diameter to a larger diameter, thus gripping thebronchial lumen wall. Alternately, the shunt tubes may comprise adeformable retainer that is expanded to grip the bronchial lumen wall byinflating a balloon placed inside the collapsed shunt tube. The shunttubes may also comprise a cylindrical structure that increases indiameter when its temperature is raised to body temperature. The shunttubes may also have barbs, prongs or other features on the outside thatassist in gripping the bronchial lumen wall for retention.

Exemplary Bronchial Isolation Devices

As discussed above, a target lung region can be bronchially isolated byadvancing a bronchial isolation device into the one or more bronchialpathways that directly feed air to the targeted lung region. Thebronchial isolation device can be a device that regulates the flow offluid into or out of a lung region through a bronchial passageway. FIG.19 shows a cross-sectional view of an exemplary bronchial isolationdevice comprised of a flow control element 1910. It should beappreciated that the flow control element 1910 is merely an exemplarybronchial isolation device and that other types of bronchial isolationdevices for regulating air flow can also be used. For example, thefollowing references describe exemplary bronchial isolation devices:U.S. Pat. No. 5,594,766 entitled “Body Fluid Flow Control Device; U.S.patent application Ser. No. 09/797,910, entitled “Methods and Devicesfor Use in Performing Pulmonary Procedures”; and U.S. patent applicationSer. No. 10/270,792, entitled “Bronchial Flow Control Devices andMethods of Use”. The foregoing references are all incorporated byreference in their entirety and are all assigned to Emphasys Medical,Inc., the assignee of the instant application.

With reference to FIG. 19, the flow control element 1910 is in the formof a valve with a valve member 1915 supported by a ring 1920. The valvemember 1915 is a duckbill-type valve and has two flaps defining anopening 1925. The valve member 1915 is shown in a flow-preventingorientation in FIG. 19 with the opening 1925 closed. The valve member1915 is configured to allow free fluid flow in a first direction (alongarrow A) while controlling fluid flow in a second direction (along arrowB). In the illustrated embodiment, fluid flow in the direction of arrowB is controlled by being completely blocked by valve member 1915. Thefirst and second directions in which fluid flow is allowed andcontrolled, respectively, can be opposite or substantially opposite eachother, such as is shown in FIG. 19. The valve member 1915 functions as aone-way valve by completely blocking fluid flow in a certain direction.It should be appreciated that the flow control element could beconfigured to block or regulate flow along two-directions.

FIGS. 20 and 21 show another embodiment of an exemplary flow controlelement, comprising flow control element 2000. The flow control element2000 includes a main body that defines an interior lumen 2010 throughwhich fluid can flow along a flow path. The flow of fluid through theinterior lumen 2010 is controlled by a valve member 2012. The valvemember 2112 in FIGS. 20-21 is a one-way valve, although two-way valvescan also be used, depending on the type of flow regulation desired.FIGS. 22-25 show an exemplary two-way valve member 2500.

With reference again to FIGS. 20-21, the flow control element 2010 has ageneral outer shape and contour that permits the flow control device2010 to fit entirely within a body passageway, such as within abronchial passageway. The flow control member 2000 includes an outerseal member 2015 that provides a seal with the internal walls of a bodypassageway when the flow control device is implanted into the bodypassageway. The seal member 2015 includes a series ofradially-extending, circular flanges 2020 that surround the outercircumference of the flow control device 2000. The flow control device2000 also includes an anchor member 2018 that functions to anchor theflow control device 2000 within a body passageway. It should beappreciated that other types of flow control devices can also be used tobronchially isolate the targeted lung region.

The flow control element can be implanted in the bronchial passagewayusing a delivery catheter. According to this process, the flow controlelement is mounted on a distal end of the delivery catheter. The distalend of the delivery catheter is then deployed to the bronchialpassageway, such as by inserting the delivery catheter through thepatient's mouth or nose, through the trachea, and through the bronchialtree to the desired location in the bronchial passageway. The deliverycatheter can be deployed, for example, using a guide wire or without aguide wire. In one embodiment, a bronchoscope is deployed to thelocation in the bronchial passageway where the flow control device willbe deployed. The delivery catheter with the flow control element is thendeployed to the bronchial passageway by inserting the delivery catheterthrough a working channel of the bronchoscope such that the distal endof the delivery catheter and the attached flow control element protrudefrom the distal end of the working channel into the bronchialpassageway. The flow control element is then removed from the deliverycatheter so that the flow control elements is positioned within andretained in the bronchial passageway. U.S. patent application Ser. No.10/270,792, entitled “Bronchial Flow Control Devices and Methods of Use”(which is assigned to Emphasys Medical, Inc., the assignee of theinstant application) describes various methods and devices forimplanting a flow control element into a bronchial passageway.

Although embodiments of various methods and devices are described hereinin detail with reference to certain versions, it should be appreciatedthat other versions, embodiments, methods of use, and combinationsthereof are also possible. Therefore the spirit and scope of theappended claims should not be limited to the description of theembodiments contained herein.

1. A method of treating a patient's lung region, comprising: deploying acatheter into a lung; using the catheter to apply heat to a targetedlung region wherein the heat affects fluid flow within the targeted lungregion.
 2. A method as in claim 1, wherein the heat reduces orterminates fluid flow within the targeted lung region.
 3. A method as inclaim 1, wherein the heat generates a reaction in tissue of the targetedlung region that results in a reduction or prevention of fluid flowwithin the targeted lung region.
 4. A method as in claim 1, wherein theheat seals portions of the lung together.
 5. A method as in claim 1,wherein the heat scleroses lung tissue within the targeted lung region6. A method as in claim 1, wherein the heat promotes fibrosis in oraround the targeted lung region
 7. A method as in claim 1, wherein theheat creates an inflammatory response in the targeted lung region.
 8. Amethod as in claim 1, wherein the heat affects fluid flow by reducing orpreventing collateral fluid flow into the targeted lung region.
 9. Amethod as in claim 1, wherein deploying a catheter into a lung comprisesdeploying a catheter through a bronchial tree into the targeted lungregion such that a distal end of the catheter is positioned near thetargeted lung region.
 10. A method as in claim 9, wherein the heat isapplied via the distal end of the delivery catheter.